Summary: Research in my laboratory is focused on understanding how two human adenovirus (Ad) genes (E1A and E1B) modulate both the host innate immune response and cell death pathways. The ultimate goal of our research is to develop novel treatments for virus induced acute respiratory distress syndrome (ARDS). We have described a novel, immunorepressive activity of Ad infected dying cells (termed Ad CPE corpses) that modulate the Ad-induced, innate immune response. Ad CPE corpse repression of macrophage-mediated inflammatory responses requires expression of the Ad protein, E1B 19/20K. Ad CPE corpses resulting from infection with Ad that lack E1B 19K, fail to repress Ad-induced macrophage pro-inflammatory responses and, in contrast, can induce increases in such responses. Ad14p1 is an emergent strain of Ad14 that induces a strong inflammatory response during infection that can result in severe, acute lung injury and, in some cases, ARDS. Studies showed reduced E1B 20K expression in virally infected human cells, when compared with wild type (wt) Ad14 infection. As a result, Ad14p1 CPE corpses fail to repress pro-inflammatory macrophage responses, whereas wt Ad14 CPE corpses are markedly immunorepressive. Syrian hamsters are permissive for human adenoviruses. Infection of Syrian hamsters revealed that Ad14p1 infection induces a patchy bronchopneumonia that is not seen following infection with Ad14. Ad14p1 infected hamsters also show up-regulation of pro-inflammatory cytokines, consistent with our in vitro model system. Currently, we are developing new methods to characterize the innate immune response in the lungs of Ad14p1 lungs and testing novel mechanisms through which Ad14 CPE corpses repress pro-inflammatory macrophage responses. With the goal to developing novel methods to treat viral and non-viral induced ARDS.

Minimum classes: Basic biology and chemistry courses

Projects: Understanding how emergent adenovirus strains induce increased disease requires studying both the virus and host responses to viral infection. Project 1: Understanding how viral gene expression alters pathogenesis requires us to make adenoviruses that express either mutated forms of the normal proteins or that express different amounts of the normal protein. Project 2: Infection of tissue culture cells with Ad14p1 results in altered expression of host miRNA profiles compared to miRNA expression profiles following Ad14 infection. To complement these studies we would like to explore if similar changes happen during infection of primary epithelial cells.

Project 1) Creation of recombinant adenoviruses. Techniques would include: PCR, bacterial cell culture, homologous recombination, eukaryotic cell culture, adenoviral growth and purification.

Project 2) Studies on host miRNA expression during adenovirus infection. Techniques would include: Eukaryotic cell culture, adenoviral infection of cells, miRNA isolation from cells, quantitation of miRNA by qRT-PCR and determining target protein expression by western blot.

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